Cabrini, L., Brusasco, C., Roasio, A., Corradi, F., Nardelli, P., Filippini, M.,Cotticelli, V., Belletti, A., Ferrara, L., Antonucci, E., Baiardo Redaelli, M.,Lattuada, M., Colombo, S., Olper, L., Ponzetta, G., Ananiadou, S., Monti, G.,Severi, L., Maj, G., ... Landoni, G. (2019). Non-invAsive VentIlation forearly General wArd respiraTory failurE (NAVIGATE): A multicenterrandomized controlled study. Protocol and statistical analysis plan.Contemporary Clinical Trials, 78, 126-132.https://doi.org/10.1016/j.cct.2019.02.001

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Accepted Manuscript

Non-invAsive VentIlation for early General wArd respiraToryfailurE (NAVIGATE): A multicenter randomized controlled study.Protocol and statistical analysis plan

Luca Cabrini, Claudia Brusasco, Agostino Roasio, FrancescoCorradi, Pasquale Nardelli, Matteo Filippini, Virginia Cotticelli,Alessandro Belletti, Lorenzo Ferrara, Elio Antonucci, MartinaBaiardo Redaelli, Marco Lattuada, Sergio Colombo, Luigi Olper,Giuseppe Ponzetta, Sofia Ananiadou, Giacomo Monti, LucaSeveri, Giulia Maj, Giuseppe Giardina, Giuseppe Biondi Zoccai,Umberto Benedetto, Marco Gemma, Sarah Sophia MichelleCavallero, Ludhmila Abrahao Hajjar, Alberto Zangrillo, RinaldoBellomo, Giovanni Landoni

PII: S1551-7144(18)30637-2DOI: https://doi.org/10.1016/j.cct.2019.02.001Reference: CONCLI 5740

To appear in: Contemporary Clinical Trials

Received date: 8 November 2018Revised date: 31 January 2019Accepted date: 6 February 2019

Please cite this article as: L. Cabrini, C. Brusasco, A. Roasio, et al., Non-invAsiveVentIlation for early General wArd respiraTory failurE (NAVIGATE): A multicenterrandomized controlled study. Protocol and statistical analysis plan, Contemporary ClinicalTrials, https://doi.org/10.1016/j.cct.2019.02.001

This is a PDF file of an unedited manuscript that has been accepted for publication. Asa service to our customers we are providing this early version of the manuscript. Themanuscript will undergo copyediting, typesetting, and review of the resulting proof beforeit is published in its final form. Please note that during the production process errors maybe discovered which could affect the content, and all legal disclaimers that apply to thejournal pertain.

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Non-invAsive VentIlation for early General wArd respiraTory failurE (NAVIGATE): a multicenter

randomized controlled study. Protocol and statistical analysis plan.

Luca Cabrinia, Claudia Brusascob, Agostino Roasioc, Francesco Corradib,d, Pasquale Nardellia,

Matteo Filippinie, Virginia Cotticellif, Alessandro Bellettia, Lorenzo Ferrarag, Elio Antonuccih,

Martina Baiardo Redaellia, Marco Lattuadab, Sergio Colomboa, Luigi Olpera, Giuseppe Ponzettaa,

Sofia Ananiadoui, Giacomo Montia, Luca Severij, Giulia Majk, Giuseppe Giardinaa, Giuseppe Biondi

Zoccail,m, Umberto Benedetton, Marco Gemmao, Sarah Sophia Michelle Cavalleroc, Ludhmila

Abrahao Hajjarp, Alberto Zangrilloa,q, Rinaldo Bellomor,s,t, Giovanni Landonia,q,*

landoni.giovanni@hsr.it

aDepartment of Anesthesia and Intensive Care, IRCCS San Raffaele Hospital, Milan, Italy

bDepartment of Anesthesia and Intensive Care, EO Ospedali Galliera, Genova, Italy

cDepartment of Anesthesia and Intensive Care, Ospedale Civile di Asti, Asti, Italy

dUniversità degli Studi di Pisa, Pisa, Italy

eDepartment of Anesthesia and Critical Care Medicine, Spedali Civili, Brescia, Italy

fDepartment of Anesthesia and Intensive Care, Aurelia Hospital, Roma, Italy

gDepartment of Pneumology, Ospedale Villa Scassi ASL 3 Genovese, Genova, Italy

hDepartment of Emergency-Urgency Medicine, Ospedale Guglielmo da Saliceto, Piacenza, Italy

iDepartment of Anesthesia and Intensive Care, ASST Cremona, Cremona, Italy

jDepartment of Anesthesia and Intensive Care, Azienda Ospedaliera San Camillo Forlanini, Roma,

Italy

kDepartment of Anesthesia and Intensive Care, Sant'Antonio e Biagio e Cesare Arrigo Hospital,

Alessandria, Italy

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lDepartment of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome,

Latina, Italy

mIRCCS NEUROMED, Pozzilli (IS), Italy

nBristol Heart Institute, University of Bristol, School of Clinical Sciences, Bristol, United Kingdom

oDepartment of Anesthesia and Intensive Care - Ospedale Fatebenefratelli (ASST Fatebenefratelli-

Sacco), Milan, Italy

pDepartment of Cardiopneumology, Heart Institute, Faculty of Medicine, University of Sao Paulo,

Hospital Siriolibanes, Sao Paulo, Brazil

qVita-Salute San Raffaele University Milan, Italy

rIntensive Care Unit, Wellington Regional Hospital, Wellington, New Zealand.

sAustralian and New Zealand Intensive Care Research Center, Monash University, Melbourne, VIC,

Australia.

tSchool of Medicine, University of Melbourne, Melbourne, VIC, Australia

*Corresponding author at: Department of Anesthesia and Intensive Care, San Raffaele Hospital, Via

Olgettina 60 Milan, 20132 Italy.

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ABSTRACT

Objective

Few randomized trials have evaluated the use of non-invasive ventilation (NIV) for early acute

respiratory failure (ARF) in non-intensive care unit (ICU) wards. The aim of this study is to test the

hypothesis that early NIV for mild-moderate ARF in non-ICU wards can prevent development of

severe ARF.

Design

Pragmatic, parallel group, randomized, controlled, multicenter trial.

Setting

Non-intensive care wards of tertiary centers.

Patients

Non-ICU ward patients with mild to moderate ARF without an established indication for NIV.

Interventions

Patients will be randomized to receive or not receive NIV in addition to best available care.

Measurements and main results

We will enroll 520 patients, 260 in each group. The primary endpoint of the study will be the

development of severe ARF. Secondary endpoints will be 28-day mortality, length of hospital stay,

safety of NIV in non-ICU environments, and a composite endpoint of all in-hospital respiratory

complications.

Conclusions

This trial will help determine whether the early use of NIV in non-ICU wards can prevent

progression from mild-moderate ARF to severe ARF.

Keywords: NIV; Non-invasive ventilation; acute respiratory failure; ARF

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INTRODUCTION

Non-invasive ventilation (NIV), a technique to deliver positive pressure ventilation through a non-

invasive interface, is used worldwide to prevent and treat acute severe respiratory failure (ARF).

(1–3) For this purpose, it is an intervention with a well-documented effect on survival in critically

ill patients. (4) There are increasing reports on the effective use of NIV outside the ICU (5–9). In

this regard, the use of NIV in general wards may be cost-effective (10) and may allow treatment of

patients at an earlier stage of ARF. (3, 11)

Moreover, it is logical to hypothesize that the use of NIV in the early phases of ARF (when ARF is

mild to moderate in severity) may be beneficial for patients outside ICUs and may avoid the

development of severe ARF with its associated need for ICU admission and invasive mechanical

ventilation (MV). To date, however, randomized studies of such “early” NIV use for ARF are few

and limited to the setting of immunocompromised patients. (12, 13)

Accordingly, we designed a controlled trial to test the hypothesis that the addition of early NIV to

standard care in patients with mild to moderate ARF could reduce the rate of disease progression.

RATIONALE

ARF is the most frequent cause of deterioration in hospitalized patients assessed by medical

emergency teams. (14) There is good evidence of benefit with the use of NIV in specific etiologies

of ARF such as acute exacerbation of chronic obstructive pulmonary disease (COPD) (15, 16) and

cardiogenic pulmonary edema (17–19), and conflicting evidence in other causes of ARF, such as

hypoxemic respiratory failure (20) and ARF in immunocompromised patients. (21-23) However,

there is also meta-analytic evidence of a beneficial effect in ARF regardless of etiology. (24)

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Most studies on the effect of NIV, however, have taken place in intensive care units (ICUs), as this

is the appropriate setting for severe ARF and because in the ICU there is maximal expertise on

ventilation and adequate equipment. Thus, the ICU environment provides safer and perhaps more

effective treatment for patients with moderate or severe ARF.

Use of NIV as an early therapy in mild to moderate ARF to prevent progression to severe ARF,

albeit appealing, has been the object of only a few small trials and mixed evidence. A small trial

conducted by Hilbert et al. on 52 patients found reduced intubation rates and increased survival in

ICU patients treated with NIV compared to usual care in early ARF. (21) A second trial, involving 40

ICU patients and comparing standard care with NIV in early ARF, showed that NIV was associated

with a reduction in intubation rate, fatal complications and ICU length of stay, but not with better

hospital survival. (25) More recently, however, Lemiale et al. performed a larger trial on 374 ICU

patients, showing no difference in 28-day mortality between early NIV and standard care for ARF.

(23) These trials, however, were all conducted in the ICU.

Only two trials were conducted outside the ICU. Squadrone et al. randomized 40 patients on a

hematology ward to either standard care or early use of NIV in ARF, showing a reduced

progression of disease in the latter group. (12) Wermke et al. randomized 86 patients with ARF to

standard therapy or standard therapy with the addition of NIV and found no difference in

progression of disease or mortality. (13) However, as reported by the authors, these trials were

underpowered to demonstrate differences between the two groups.

In this regard, our trial will be the largest trial on the early use of NIV outside the ICU in patients

with mild to moderate ARF, with greater power to demonstrate a difference in the rate of

development of severe ARF.

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MATERIALS AND METHODS

Study design, approval and registration

We designed a parallel group, randomized, controlled, multicenter trial with a 1:1 allocation ratio.

The study was approved by the Human Research Ethics Committees of all participating centers

and was registered on clinicaltrials.gov as NCT01572337 on April 6, 2012.

Study aim

The main aim of the study was to test whether the use of NIV in the early stages of ARF could

reduce disease progression when compared to usual care. Secondary endpoints of the study

aimed to evaluate the impact of early NIV on 28-day mortality and on length of hospital stay.

Study population/Participants

We will enroll 520 adult patients with mild to moderate ARF admitted to a non-intensive-care

ward. The inclusion and exclusion criteria are summarized in Table 1. Contraindications to NIV

include respiratory arrest, inability to fit mask, hypotensive shock, ongoing cardiac ischemia or

arrhythmia, copious upper gastrointestinal bleeding, uncooperating patient, inability to protect

airway, swallowing impairment, excessive secretions, multiple organ failure, recent facial, upper

airway or upper gastrointestinal surgery, facial trauma/burns, life threatening hypoxemia,

vomiting, bowel obstruction, undrained pneumothorax. (3,26) The aim of these criteria is to

identify a group of patients with very early mild to moderate ARF and to exclude those patients

who have an already established clear indication for NIV. The only etiologic exclusion criteria is

COPD exacerbation (in which NIV is considered mandatory); in all other cases, inclusion and

exclusion criteria are essentially based on the severity of ARF and not on its cause.

Study procedure

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The study procedure is summarized in Figure 1. Patients with mild to moderate ARF (defined as at

least one of the following criteria: radiological evidence of new pulmonary consolidation or

atelectasis; peripheral oxygen saturation <92% while breathing room air or PaO 2/FiO2 ratio < 300

but >200 on arterial blood gas analysis; decompensated hypercapnia (pCO2 > 45 mmHg and pH <

7.35) or clinical signs of respiratory distress (dyspnea, utilization of accessory respiratory muscles,

paradoxical movement of thoraco-abdominal wall) on room air will be screened for eligibility. If

eligible, they will then be approached to explain the study protocol and obtain written informed

consent. Once the informed consent has been signed, patients will be allocated to each study

group according to a web-based centralized randomization service with the use of a permuted-

block design stratified according to center. Data will be collected by trained observers who will not

participate in patient care.

Patients randomized to the “usual care” group will receive the best available treatment currently

in use in the institution, including oxygen therapy, diuretics, antibiotics and other therapies to

treat the underlying cause of the ARF. Patients in this group will not receive NIV treatment unless

the medical emergency team deems it necessary. If NIV is administered outside of such

restrictions, this will represent a protocol violation.

Patients assigned to the “early NIV” group will receive the same best available treatment as the

“standard” group, together with two-hour cycles of NIV every eight hours.. Oro-nasal, full-face and

helmet NIV interface will be allowed. The preferred NIV treatment will be CPAP (PEEP 5 to 8

cmH2O) unless the ARF is hypercapnic at enrollment or in the following days. In such cases

pressure support ventilation (with a pressure support of 10 to 20 cmH2O) will be added.

Ventilatory parameters will be set (and then modified if required) by physicians on the basis of

clinical judgment and on the basis of the patient’s response to the treatment with the aim of

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reaching a peripheral oxygen saturation >92% and PaCO2 <45 mmHg, without restrictions,

according to the pragmatic nature of the study. Chosen settings will be recorded.

The Medical Emergency Team (MET) was responsible for setting-up and initial deliver of NIV in

accordance with the physicians of the ward. MET always included an anesthesiologist-intensivist

and a nurse and/or a fellow, differing in the various participating hospitals). Monitoring of

uncomplicated patients is performed by the ward staff.

Patients will be evaluated before starting each NIV cycle. Treatment with NIV will continue until at

least one of the following criteria is met:

Clinical improvement determined by the resolution of inclusion criteria;

Patient refusal of treatment due to intolerance, or consent withdrawal;

Clinical decision of NIV interruption for NIV contraindication or other reasons

Development of severe ARF defined by one or more of the following criteria:

o Hypercapnic acidemia (PaCO2 > 45 mmHg and pH < 7.30)

o Severe gas transfer deficit (PaO2/FiO2 < 200)

o Persistent respiratory distress (persistent marked dyspnea, use of accessory

respiratory muscles, paradoxical respiratory movements)

Post-randomization decision/diagnosis of extremely poor short-term prognosis (imminent

death with decision for palliative treatment only), with withdrawal of non-palliative

treatment;

Need for immediate invasive mechanical ventilation

ICU admission

Death

Treatment with NIV will last for at least 24 hours (3 cycles) unless interruption criteria (with the

exception of clinical improvement) are met.

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Target peripheral oxygen saturation will be 92-95% in both groups. Clinical re-evaluation (inclusive

of re-checking for inclusion and exclusion criteria) will be performed daily by the medical

emergency team or more often if deemed necessary by the ward physicians.

As the protocol is carried in general wards, an arterial catheter is never positioned. Arterial blood

gas analyses are only performed upon clinical judgement by means of single shot arterial

punctures.

NIV treatment will continue for 4-day periods. At the end of each period, patients will undergo a 6-

h screening test during which they will breath room air. If their SaO2 decreases below 95%, or the

respiratory rate increases to > 25 breaths/min, patients will be returned to the assigned treatment

for another 4-day period. The treatment protocol will be discontinued when the patient has a

SaO2 > 95% and respiratory rate < 25 breaths/min. (12) This does not apply to patients who have

already reached the primary endpoint or one of the above-mentioned reasons for NIV

discontinuation. (Figure 2)

Data collection

We will collect demographic data (age, sex), as well as baseline pathophysiological data (height,

weight, comorbidities). Two independent Investigators will assess and record the main cause of

acute respiratory failure, as well as concomitant causes and the therapy the patient is receiving.

Vital signs (respiratory rate, peripheral oxygen saturation, Glasgow Coma Score, arterial blood

pressure, heart rate) and arterial blood gas data (where available) will be recorded at all scheduled

time points if the patient will be not yet discharged from the hospital. Information on ventilator

parameters, along with complications and potential contraindications to NIV treatment, will also

be collected.

Follow-up will be performed at 28, 90 and 365 days after randomization either via direct visit or

telephone call.

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Individual participant data that underlie the results reported in the trial’s final results article, after

deidentification, agreement of the privacy office of the Institute and ethical committee approval

will be shared upon request 9 months to five years after the publication of the trial’s final results.

Study protocol and informed consent form will also be available upon request. Requesters must

have a demonstrated experience in medical research, with no conflict of interest that may

potentially influence their interpretation of any analyses . The data sharing will be only for the

purposes of health and medical research and within the constraints of the consent under which

the data were originally gathered. Requester will be required to enter into a Data Sharing

Agreement which will follow the Ethical Committee and Privacy Office updated indications

Study endpoints/ Outcomes

According to the recommendations of the European Society of Anaesthesiology (ESA) and the

European Society of Intensive Care Medicine (ESICM) joint task force (27), the study will also focus

on clinically relevant outcomes such as mortality, need for invasive mechanical ventilation, length

of hospital stay and ICU admission.

The primary outcome will be the development of severe ARF defined by one or more of the

criteria described above. Prespecified subgroups analyses for the primary endpoint will be: age<75

years old; 20<=BMI<30 kg/m2; respiratory rate<25 per minute; postoperative patients .

Secondary outcomes will include 28-day mortality, length of hospital stay, as well as a composite

endpoint of all in-hospital respiratory complications (comprising atelectasis, nosocomial

pneumonia, new pneumothorax, pleural effusion, intubation, tracheostomy and acute respiratory

distress syndrome as defined by the Berlin definition). (28)

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Atelectasis will be defined as lung opacification with a shift of the mediastinum, hilum or hemi-

diaphragm, and compensatory over inflation in the adjacent non- atelectatic lung. (29)

Nosocomial pneumonia will be defined as two or more serial chest radiographs with at least one

of the following findings (one radiograph is sufficient for patients with no underlying pulmonary or

cardiac disease): (i) New or progressive and persistent infiltrates, (ii) consolidation, (iii) cavitation;

AND at least one of the following: (a) fever (>38 °C) with no other recognized cause, (b) leukopenia

(white cell count <4x109/liter) or leukocytosis (white cell count >12x109/liter), (c) for >70-year old

adults, altered mental status with no other recognized cause; AND at least two of the following:

(a) new onset of purulent sputum or change in character of sputum, or increased respiratory

secretions, or increased suctioning requirements, (b) new onset or worsening cough, or dyspnea,

or tachypnoea, (c) rales or bronchial breath sounds, (d) worsening gas exchange (hypoxemia,

increased oxygen requirement, increased ventilator demand) occurring more than 48 hours after

hospital admission and not appearing to be incubating at the time of admission. (30)

Pneumothorax will be defined as air in the pleural space with no vascular markings surrounding

the visceral pleura. (29)

Pleural effusion will be defined as chest X-ray demonstrating blunting of the costo-phrenic angle,

loss of the sharp silhouette of the ipsilateral hemi-diaphragm when upright, displacement of

adjacent anatomical structures, or a hazy opacity in one hemithorax with preserved vascular

shadows when supine. (29)

Statistical analysis and sample size estimates

Data will be collected by the investigators and stored electronically in a digital Excel spreadsheet

(version 2010, Microsoft Corporation, Redmond, WA, USA) and analyzed using STATA (Stata

Statistical Software: version 15, College Station, TX, USA). Statistical analysis will be performed by

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an epidemiologist. All analysis will be performed by an independent statistician blinded to

intervention allocation. We will not apply any imputation for missing data. All data will be

analyzed according to the intention-to-treat principle. The only exception will be those patients

that, after randomization, are declared terminally ill and only receive palliative interventions: this

decision will be taken as standard practice by the MET in conjunction with the caring ward staff

and shared with the patient and his/her family.

Demographic and baseline disease characteristics will be summarized with the use of descriptive

statistics. Categorical variables will be reported as absolute numbers and percentages. Unadjusted

univariate analyses to compare the two groups will be performed using Pearson’s χ2 test or

Fisher’s exact test as appropriate. Risk differences and 95% confidence intervals will be calculated

by means of the two-by-two table. Continuous variables will be reported as mean ± standard

deviation or median and interquartile range, based on the distribution. Normality will be

evaluated with the Shapiro-Wilk normality test, along with visual histogram evaluation and a Q-Q

plot, and differences between groups will be tested using Student’s T test or the Wilcoxon signed

rank test, as appropriate.

A logistic regression model using a stepwise selection will be used to estimate the treatment

effect with respect to primary and secondary endpoints and predictors of mortality. The pre-

randomization clinical data (e.g. demographic and baseline pathophysiological data) and center

will be entered into the model if their univariate p value is less than 0.2. Collinearity and

overfitting will be assessed using a stepwise regression model and Pearson correlation test. The

treatment group will be forced into the multivariate model. A classic logistic regression will be

performed with a consistent number of events and the number of covariates in the model will be

decided based on the number of outcome events. In the multivariate analyses, clinical factors or

potential confounding variables will be expressed as odds ratio with 95% confidence interval (CI).

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We will compare patients receiving NIV with those assigned to standard care for time to event

with the log-rank test and display such comparison with Kaplan-Meier survival curves. A time to

event analysis with a Cox regression will be performed to adjust for key baseline characteristics .

Two interim analyses performed by an independent safety committee after recruiting 25% (n=130)

and 50% (n=260) of patients are planned. Data evaluation at each interim analysis will be based on

the alpha spending function concept, according to DeMets, (31) and will employ O’Brien-Fleming

Z-test boundaries. (32) During the first interim analysis the efficacy stopping rule will require a p

value (p < 0.005), while a higher value (p < 0.014) will be required for the second analysis.

Investigators will be kept blind to the interim analysis results.

The independent safety committee will also perform conditional power analyses in order to

evaluate potential interruption for futility issues in the trial. Conditional power will be calculated

by assuming that the proportion of outcomes will follow the observed trend.

Based on available literature,(12,13) we have hypothesized that the primary endpoint will be

reached by 22% of patients in the “usual care” group and in 11% of patients in the “early-NIV”

group. We based the sample size computation on a two-sided alpha error of 0.05 and a power of

90% using Pearson’s χ2 test. Therefore, we calculated 256 patients per group using the continuity

correction (260 considering possible protocol deviations) for a total of 520 patients.

Monitoring of the study

Study auditors will verify the strict adherence to the clinical trial protocol and will confirm accurate

data collection according to Good Clinical Practice guidelines. (33) Study monitoring and follow-up,

from initial set-up to final reporting, will be fulfilled according to national and international

requirements.

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Ethical aspects

It is important to evaluate the role of early initiation of NIV in addition to standard therapy as this

may prevent progression to severe ARF in patients, as previously reported, (12,15,33) and

consequently might improve outcomes and reduce healthcare costs.

The exclusion of patients with acute exacerbation of COPD is due to the fact that NIV is first-line

therapy in these patients (26) and it would be unethical to deprive them of this treatment. Data

will be stored in an electronic database with no patient identifiers (a unique numeric code will be

used) to address privacy issues.

Study initiation, timing and participating centers, source of funding

The study started after Ethical Committee approval from each contributing recruiting center.

Recruitment started in April 2012 as a single center trial to assess feasibility. The study became

multicentric in 2016. Consecutive participants who meet eligibility criteria and sign the written

informed consent are enrolled. The study progress will be updated monthly. Currently, six

hospitals have randomized a total of 175 patients.

The authors are solely responsible for the design and conduct of the study, all study analyses and

drafting and editing of the final research paper.

The trial is funded with departmental funds only.

EXPECTED RESULTS

In the present study, we will test the hypothesis that the early addition of NIV in non-ICU patients

with mild-moderate ARF would reduce development of severe ARF from 22% to 11%. Our trial will

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help determine whether NIV can play a wider role in the treatment of ARF than it currently does,

possibly reducing short-term mortality and length of hospital stay.

Limitations

A possible limitation of the study is the absence of a strictly defined “usual care” in the control

group, leaving the definition of best available treatment to the single participating centers. We

believe, however, that this pragmatic approach can also be seen as a strength of our study, which

will allow us to capture the complex reality of tertiary centers and allow each patient to be treated

according to best available local expertise and logistics. In this context, for example,

echocardiography is only performed in those with a positive history or clinical features of cardiac

dysfunction (severe right ventricular dysfunction is a contraindication to NIV) and lung ultrasound

for pleural effusion is only performed at discretion of clinicians caring for the patients .

Moreover, as the study will take place in ordinary, non-intensive general medical or surgical

wards, that do not have the resource and staffing of ICUs, we anticipate that the adherence to

study protocols, both by patients and by staff, may not be perfect. However, we believe this is also

a potential strength of the study, as it would investigate and measure use of NIV in a “real world”

environment and not solely as part of a tightly controlled experimental protocol. Furthermore,

due to the nature of NIV treatment, blinding is not an option in this setting. Also, the exclusion

criteria cut out from the present study some of the patients who might benefit more from NIV:

COPD exacerbation. As NIV has been already demonstrated extremely beneficial in this setting, in

many centers, it is used immediately as first-line therapy in this population. Therefore, we decided

to exclude these patients, even if this may reduce the magnitude of our findings. However, this

might be seen as a strength more than a limitation, as it'is more ethical and improves the validity

of our eventual positive findings. Lastly, the hypothesized effect size might be considered too big,

but we considerate it very prudential since, following the results of Squadrone et al (12) the

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sample size should have been 49 patients per group only and following the results of Wermke et

al., (13) the sample size should have been 213 per group. Our prudential decision of enrolling 520

patients is driven by the heterogeneity of our population, that represents the daily complexity of

large hospitals.

CONCLUSIONS

This will be the first large randomized controlled trial performed outside the ICU and comparing

the effect of the early addition of NIV to usual care in patients with mild to moderate ARF.

Evidence resulting from this study will potentially be of value in the effective early management of

patients with ARF.

Conflict of interest

The authors declare no conflict of interest

Acknowledgments

We’d like to thank Giuseppe Dalessandro, LT, Laura De Simone, RN, Camilla Baranzini, RN, Cristina

Ceresa, RN, Margherita Savini, RN, Federica Parmigiani, RN, Piero Masciullo, RN, Annalisa Fanton,

RN, Lorenzo Trotti, RN, Sara Gargano, RN for their help, constant effort and contribute and for

making this study possible.

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Table 1 – Inclusion and Exclusion criteria. Inclusion criteria (all three have to be

present)

Exclusion criteria (one is sufficient to

exclude the patient)

Age > 18 years;

Admission to non-intensive-care department;

Mild to moderate ARF, defined as at

least one of the following: o Radiological evidence of new

pulmonary consolidation or

atelectasis;

o Peripheral oxygen saturation <92%

while breathing room air or PaO2/FiO2 ratio < 300 on arterial

blood gas analysis;

o Decompensated hypercapnia (pCO2

> 45 mmHg and pH < 7.35);

o Clinical signs of respiratory distress (dyspnea, utilization of accessory

respiratory muscles, paradox

movements of thoraco-abdominal

wall) on room air.

Refusal to sign informed consent

Respiratory failure due to COPD exacerbation (PaCO2 > 45 mmHg and

pH < 7.35);

Severe, hypercapnic ARF defined as PaCO2 > 45 mmHg and pH <7.30;

Severe, hypoxic ARF defined as

PaO2/FiO2 <200;

Need for immediate mechanical ventilation or ICU as judged by the ICU

physician in charge;

Extremely poor short-term prognosis (imminent death with decision for

palliative treatment only);

Invasive or non-invasive mechanical

ventilation during the same hospitalization due to respiratory

failure.

Contraindications to NIV treatment (3,

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26)

ARF – Acute Respiratory Failure; COPD – Chronic Obstructive Pulmonary Disease; ICU – Intensive Care Unit.

Figure 1 Study procedure flowchart. NIV – Non-invasive ventilation.

Figure 2 Intervention diagram.

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Figure 1

Figure 2